The dependency of purified mouse cerebellar type 1 inositol 1,4,5-trisphosphate receptor (IP₃R1)/Ca²⁺ channel function on cytoplasmic Ca²⁺ was examined. In contrast to the channels in crude systems, the purified IP₃R1 reconstituted into planar lipid bilayers did not show the bell-shaped dependence on Ca²⁺. It was activated with increasing Ca²⁺ sublinearly without inhibition even up to 200 μM. The addition of calmodulin to the cytoplasmic side inhibited the channel at high Ca²⁺ concentrations. Calmodulin antagonists reversed the Ca²⁺-dependent inactivation of the native channels in cerebellar microsomes. These results indicate that the bell-shaped dependence on cytoplasmic Ca²⁺ is not an intrinsic property of the IP₃R1, and the Ca²⁺-dependent inactivation is directly mediated by calmodulin.